In blood, the primary role of red blood cells (RBCs) is to transport oxygen via highly regulated mechanisms involving hemoglobin (Hb). Hb is a tetrameric porphyrin protein comprising of two alpha- and two beta-polypeptide chains, each containing an iron-containing heme group capable of binding one oxygen molecule. In military as well as civilian traumatic exsanguinating hemorrhage, rapid loss of RBCs can lead to suboptimal tissue oxygenation and subsequent morbidity and mortality. In such cases, transfusion of whole blood or RBCs can significantly improve survival. However, blood products including RBCs present issues of limited availability and portability, need for type matching, pathogenic contamination risks, and short shelf-life, causing substantial logistical barriers to their prehospital use in austere battlefield and remote civilian conditions. While robust research is being directed to resolve these issues, parallel research efforts have emerged toward bioengineering of semisynthetic and synthetic surrogates of RBCs, using various cross-linked, polymeric, and encapsulated forms of Hb. These Hb-based oxygen carriers (HBOCs) can potentially provide therapeutic oxygenation when blood or RBCs are not available. Several of these HBOCs have undergone rigorous preclinical and clinical evaluation, but have not yet received clinical approval in the USA for human use. While these designs are being optimized for clinical translations, several new HBOC designs and molecules have been reported in recent years, with unique properties. The current article will provide a comprehensive review of such HBOC designs, including current state-of-the-art and novel molecules in development, along with a critical discussion of successes and challenges in this field.
